Project Summary/Abstract - Project 2 The splanchnic circulation is supplied by sympathetic nerves which control resistance and capacitance. Elevated sympathetic nerve activity (SNA) increases resistance and decreases capacitance causing increased blood pressure. Dysregulation of SNA and dilator mechanisms contribute to obesity-related hypertension. We will study how obesity disrupts molecular control of norepinephrine (NE) and ATP release at the arterial and venous sympathetic neuroeffector junction. A novel concept guiding these studies is that mesenteric perivascular fat (mPVAT) is a source of inflammatory mediators and norepinephrine (NE) that can alter sympathetic function. Specific aim 1: Prejunctional alpha2 adrenergic receptors (alpha2ARs) regulate NE and ATP release from sympathetic nerves and alpha2AR function is impaired in obesity-associated hypertension. The mechanisms responsible for impairment are linked to inflammation. We will test the hypothesis that alpha2AR function is impaired due to the action of mPVAT-derived inflammatory mediators. Specific aim 2: NE and ATP constrict and NE and endothelial derived nitric oxide (NO) relax vascular smooth muscle. Pannexin-1 is a smooth muscle ATP permeable channel and ATP contributes to arterial constriction caused by NE. This conclusion is based only on studies of exogenously applied NE; pannexin-1 contributions to neurogenic arterial or venous constriction have not been established. These studies will test the hypothesis that pannexin-1 contributes to neurogenic constriction in mesenteric arteries and veins and that pannexin-1 expression and function and NE and NO dilator mechanisms are impaired in obesity-associated hypertension. Specific aim 3: This aim will focus on neurogenic constrictions and dilator mechanisms of human mesenteric arteries and veins obtained from obese patients undergoing gastric by-pass surgery and from non-obese patients undergoing intestinal or colonic resection. In addition to studies of basic mechanisms of sympathetic constriction of arteries and veins in the human splanchnic circulation, we will identify the mechanisms responsible for disruption of vascular tone and sympathetic neuroeffector transmission in obesity.